Project Summary Our program has focused on the translation of transplantation biology from the laboratory to the clinic to improve the outcome of blood and marrow transplantation (BMT). The development high-dose post-transplant cyclophosphamide (PTCy) to modulate GVHD is a prime example of our group?s successful translational research. Not only does PTCy allow safe haploidentical (haplo) BMT in patients up to at least age 75, but results are now similar to those seen with matched donors. Accordingly, the ability to successfully utilize mismatched donors now permits virtually anyone in need of BMT to undergo the procedure. In addition to moving allogeneic BMT into non-malignant indications, our group has been concentrating on reducing relapses after allogeneic BMT for malignancy. With the reduction in non-relapse mortality, relapse has become by far the major complication of allogeneic BMT. Emerging data suggest that a new non-tolerant and non-exhausted transplanted immune system may enhance the activity of most anticancer agents. Post-allogeneic BMT maintenance therapy is already generating encouraging results; this is perhaps best exemplified by the impressive results seen in FLT3/ITD AML patients who received allogeneic BMT and post-transplant FLT3 tyrosine kinase inhibitors, despite these agents showing limited activity in the non-transplant setting. The minimal residual disease (MRD) state post-allogeneic BMT may also optimize antitumor approaches, in that they will be utilized at lowest tumor burden as well as tumor heterogeneity. Thus, we hypothesize that post- transplant maintenance may be the best strategy for decreasing relapse rates after allogeneic BMT. However, although our group and others have had successes in piloting novel clinical post-transplant maintenance strategies, it is difficult for a single program to carry out larger trials with these promising approaches. Thus, with the rapid development of promising new therapies, a formal clinical trials network that can rapidly and efficiently conduct multi-center trials in BMT is critically important. Our specific objectives as a Core Clinical Center are to: 1) Participate in multicenter trials through the BMT CTN, and 2) Propose a phase 2, multicenter, adaptively randomized trial to screen multiple novel regimens for treating relapse after allogeneic BMT for AML/MDS. An important goal will be to match individual regimens to specific disease subtypes. The ultimate goal will be to move promising approaches into post-transplant maintenance to prevent relapse. Despite remarkable progress in hematologic malignancies with most patients now responding to initial therapy, the majority eventually relapse and die of the disease. Allogeneic blood or marrow transplantation remains the only curative option for many of these patients, but relapse remains the most common cause for failure even in this setting. Novel approaches that reduce relapse without increasing toxicity are needed.